CA2596153A1 - Rimonabant-containing pharmaceutical preparation - Google Patents
Rimonabant-containing pharmaceutical preparation Download PDFInfo
- Publication number
- CA2596153A1 CA2596153A1 CA 2596153 CA2596153A CA2596153A1 CA 2596153 A1 CA2596153 A1 CA 2596153A1 CA 2596153 CA2596153 CA 2596153 CA 2596153 A CA2596153 A CA 2596153A CA 2596153 A1 CA2596153 A1 CA 2596153A1
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- pharmaceutical preparation
- solvate
- salt
- rimonabant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- 239000007788 liquid Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002210 silicon-based material Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides pharmaceutical preparations for oral administration of the active ingredient Rimonabant wherein the active ingredient is processed with a binder, a disintegrant and, optionally, additional pharmaceutical adjuvants by dry-mixing and, if necessary, by dry granulation or by direct compression, any wet granulation process being ruled out.
Description
ratiopharm GmbH
Graf-Arco-Strasse 3 89079 Ulm Rimonabant-containing Pharmaceutical Preparation The invention relates to a novel pharmaceutical preparation comprising the active ingredient 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-pyrazol-3-carboxamide which is also known under the designation Rimonabant.
The pharmaceutical preparation is prepared by dry-mixing and, optionally, direct compression (or direct compacting, respectively) or dry granulation processes.
The compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1 H-pyrazol-3-carboxamide is a well known active ingredient of the chemical formula O
H3C N,N
N H
N
CI CI
CI
Graf-Arco-Strasse 3 89079 Ulm Rimonabant-containing Pharmaceutical Preparation The invention relates to a novel pharmaceutical preparation comprising the active ingredient 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-pyrazol-3-carboxamide which is also known under the designation Rimonabant.
The pharmaceutical preparation is prepared by dry-mixing and, optionally, direct compression (or direct compacting, respectively) or dry granulation processes.
The compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1 H-pyrazol-3-carboxamide is a well known active ingredient of the chemical formula O
H3C N,N
N H
N
CI CI
CI
In older publications, the code name SR141716 is used for the compound. In EP-A 969 832, Rimonabant is still called compound A. In the meantime, however, the designation Rimonabant is common for this compound and will be used through-out this application.
Rimonabant is a selective antagonist of the cannabinoid receptor CB1. The com-pound suppresses the sensation of hunger and results in a decreased intake of food as well as a changed sugar and lipid metabolism. In addition, Rimonabant blocks the positive effects of nicotine and other psychotropic substances.
Rimo-nabant is an active ingredient which may be used especially for so-called "life-style" pharmaceutical preparations, for example for the treatment of obesity and for assisting nicotine withdrawal. Rimonabant is also considered suitable for de-creasing the triglyceride/lipid level, for treating the metabolic syndrome, for treat-ing type II diabetes and for treating arteriosclerosis. The active ingredient is also said to have positive effects on studying, sensitivity to pain, on fatty livers and Parkinson's disease. More recent data also indicate the potential use of Rimona-bant-containing pharmaceutical preparations on tumours (e.g. breast cancer, lipoma, liposarcoma). Regarding possible indications, reference may be made to EP-A 656 354 and EP-A 969 832.
Rimonabant is generically disclosed in the European patent application EP-A
576 357 and especially in the European patent application EP-A 656 354.
Rimonabant may be present in several polymorphous forms. For example, WO
2003/040105 discloses the polymorph II of the compound; and the polymorphous form I of the compound is obtained according to the process of EP-A 656 354.
With regard to the manufacturing process for Rimonabant, reference may be made to EP-A 656 354 and WO 2003/040105.
Rimonabant is a hydrophobic compound. Formulating the active ingredient to obtain solid oral pharmaceutical preparations is not without problems, because good release of the active ingredient must be guaranteed after oral administra-tion. Particularly in case of hydrophobic compounds such as Rimonabant, it is difficult to guarantee good release in the (aqueous) gastrointestinal tract after oral administration.
Rimonabant is a selective antagonist of the cannabinoid receptor CB1. The com-pound suppresses the sensation of hunger and results in a decreased intake of food as well as a changed sugar and lipid metabolism. In addition, Rimonabant blocks the positive effects of nicotine and other psychotropic substances.
Rimo-nabant is an active ingredient which may be used especially for so-called "life-style" pharmaceutical preparations, for example for the treatment of obesity and for assisting nicotine withdrawal. Rimonabant is also considered suitable for de-creasing the triglyceride/lipid level, for treating the metabolic syndrome, for treat-ing type II diabetes and for treating arteriosclerosis. The active ingredient is also said to have positive effects on studying, sensitivity to pain, on fatty livers and Parkinson's disease. More recent data also indicate the potential use of Rimona-bant-containing pharmaceutical preparations on tumours (e.g. breast cancer, lipoma, liposarcoma). Regarding possible indications, reference may be made to EP-A 656 354 and EP-A 969 832.
Rimonabant is generically disclosed in the European patent application EP-A
576 357 and especially in the European patent application EP-A 656 354.
Rimonabant may be present in several polymorphous forms. For example, WO
2003/040105 discloses the polymorph II of the compound; and the polymorphous form I of the compound is obtained according to the process of EP-A 656 354.
With regard to the manufacturing process for Rimonabant, reference may be made to EP-A 656 354 and WO 2003/040105.
Rimonabant is a hydrophobic compound. Formulating the active ingredient to obtain solid oral pharmaceutical preparations is not without problems, because good release of the active ingredient must be guaranteed after oral administra-tion. Particularly in case of hydrophobic compounds such as Rimonabant, it is difficult to guarantee good release in the (aqueous) gastrointestinal tract after oral administration.
The most common methods for preparing solid oral pharmaceutical preparations comprise a wet granulation step. Such wet granulation processes are also pro-posed in the prior art to formulate the active ingredient Rimonabant. For example, EP-A 969 832 uses the active ingredient in micronised form for preparing solid oral pharmaceutical preparations containing the active ingredient Rimonabant and formulates it into a solid oral dosage form, especially a soft gelatine capsule or a tablet, by means of a wet granulation process. In order to ensure good workability and release, a special surfactant, namely a sodium alkyl sulfate, and a very high amount of a disintegrant are required (in the range of 2.5 to 10 wt.-% in EP-A 969 832) Even though the Rimonabant-containing pharmaceutical preparations disclosed in EP-A 969 832 exhibit good release of the active ingredient, they are compli-cated to prepare. When these pharmaceutical preparations are tablets, they also have comparatively little breaking strength.
Therefore, it is the object of the present invention to provide solid pharmaceutical preparations with the active ingredient Rimonabant for oral administration the release behaviour of which is at least as good as that of the oral pharmaceutical preparations of the prior art as descibed, for example, in EP-A 969 832.
However, these pharmaceutical preparations should be easier to prepare than the pharma-ceutical preparations known from EP-A 969 832 and, when they are tablets, they should have better breaking strength than the known tablets.
This object is achieved by the subject matter of the claims.
According to the invention, it was surprisingly found that the problems in connec-tion with the release of Rimonabant from solid pharmaceutical preparations do not occur when the components are mixed in the dry state instead of using a wet granulation process for their manufacture. Optionally, dry granulation may be carried out and, especially for the preparation of tablets, direct compression (i.e.
processing of the dry mixture into tablets by direct compaction). The pharmaceu-tical preparations prepared according to the invention which are obtained by sim-ply dry-mixing the components of the pharmaceutical preparation exhibit excel-lent release profiles which meet the standards required by law, comparable with the release profiles of the pharmaceutical preparations prepared by the wet granulation process of the prior art according to EP-A 969 832. It is not necessary to use very high levels of disintegrants as deemed necessary for the wet granula-tion process of EP-A 969 832, nor is the use of an alkyl sulfate as a wetting agent or surfactant necessary for the pharmaceutical preparations of the invention to achieve the desirable high release of the active ingredient from the pharmaceuti-cal preparations. By working without a wet granulation process, advantages of process technology also result. It is obvious that wet granulation has a negative impact on the release of the active ingredient which must be offset by a large amount of disintegrant and a special surfactant. This negative impact can be avoided by processing the ingredients in the dry state without wet granulation.
Finally, it was surprising to find that better hardness of the tablets is achieved for tablets not prepared by a wet granulation process, but according to the invention by dry-mixing the components and direct compression, than the for tablets dis-closed by way of example in EP-A 969 832.
The pharmaceutical preparations of the invention contain the compound Rimo-nabant, a salt of this compound, a solvate of the compound or a solvate of a salt of this compound. Rimonabant in the form of a base or in the form of the hydro-chloride salt is especially preferred as the active ingredient. Other preferred salts of Rimonabant are the methane sulfonate, the hemifumarate, the p-toluene sul-fonate, the hydrogen sulfate, the dihydrogen phosphate, the hydrobromide, the sulfate, the methyl sulfate, the oxalate, the maleate, the fumarate, the 2-naph-thalene sulfonate, the glyconate, the gluconate, the citrate and the isethionate of the Rimonabant. Especially preferred solvates are the ethanol solvate and the acetone hemisolvate. Particularly preferred are the ethanol solvate of the hydro-chloride salts of the Rimonabant and the ethanol solvate of the Rimonabant in the form of a base. Especially the methane sulfonate may also be present as acetone hemisolvate.
As far as reference is made to Rimonabant or the "active ingredient" in the follow-ing description, this should be understood to mean Rimonabant in the form of the free base or in the form of a salt or solvate or of a solvate of the salt as described above.
The percentage of the active ingredient in the pharmaceutical preparation accord-ing to the invention is usually 0.5 to 50 wt.-%, more preferably 1 to 30 wt.-%, even more preferably 1 to 20 wt.-%, especially 5 to 20 wt.-% and most preferably to 20 wt.-%. A common dosage unit of the pharmaceutical preparation accord-ing to the invention therefore preferably contains 2 mg to 100 mg, more prefera-bly 2 mg to 60 mg, especially 15 mg to 40 mg, e.g. 10, 15, 20, 25 or 30 mg of the active ingredient.
In this application, percentages and portions are always based on the weight of the pharmaceutical preparation unless otherwise indicated or obvious from the context. If an amound of the active ingredient is mentioned, this should be under-stood to mean - in accordance with the above observation - the amount of Rimo-nabant as a base if the Rimonabant is used as a base. If the Rimonabant is used as a salt or solvate or solvate of a salt, this means the amount of the salt, the solvate or the solvate of the salt.
Rimonabant may be present in different polymorphous forms. According to the invention, any polymorphous form, any amorphous form and mixtures of poly-morphous forms with each other and with an amorphous form may be used. The polymorphous form I resulting from the method of EP-A 656 354 is especially preferred for the invention. Also preferred is the polymorph II described in WO
2003/040105. A powder diffractogram of the hydrochloride salte of the Rimona-bant prepared according to example 3 of EP-A 656 354 is enclosed as Fig. 1.
This form of the active ingredient Rimonabant is also preferred for the invention.
Rimonabant is preferabiy used in micronised form in the invention.
Micronisation can be carried out in the usual manner, for example with an air jet mill. The active ingredient particles thus micronised may, for example, be homogenised by ultra-sound treatment. While very small active ingredient particules are used for the wet granulation process, larger particles of the active ingredient may be used for the pharmaceutical preparations of the invention. Especially for the preparation of tablets by direct compression, it may be advantageous to use larger active ingre-dient particles, because the flowability and the processability of the mixture in direct compression is improved. This is another advantage of the invention, be-cause the economic and technical cost of preparing larger particles is lower than the cost of recovering very small particles.
According to the invention, it is preferred that the particle diameter of 50 %
of the active ingredient particles used (D50) is 2 NM or more, more preferably 2,5 pM
or more and especially about 3 pM. The size of 80 % of the active ingredient parti-cles (D80) should advantageously not exceed 80 pM, but preferably 50 % of the particles are not larger than 10 pM and especially not larger than 6 pM. Espe-cially preferably, the D50 value of the active ingredient particles in the pharmaceu-tical preparation of the invention is therefore in the range of 2,5 pM to 6 pM, par-ticularly about 3 pM. Within these ranges, excellent release is achieved on the one hand and good processability, especially in direct compression, on the other.
In addition to the active ingredient, the pharmaceutical preparation according to the invention also contains at least one binder and at least one disintegrant.
The suitable binders are not especially limited; the customary binders known in the prior art may be used. Especially preferred binders are copovidone, povidone, alginic acid and alginates (such as sodium alginate), cellulose and cellulose de-rivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or methyl cellu-lose and hydroxypropyl cellulose with a low level of substitution), gelatine and acrylic acid polymers. The binder copovidone is especially preferred, and the commercial product Kollidon VA 64 may be mentioned as an example. Among the povidones, the commercial product Povidon K 30 is worth mentioning.
The binder content in the pharmaceutical preparation according to the invention is not particularly limited and may be easily selected by a skilled practitioner de-pending on the particular pharmaceutical preparation. Usually the portion of the binder is the range of 0.5 to 10 10, preferably in the range of 0.5 to 5%, espe-cially in the range of 1 to 5%.
The disintegrant used is not particularly limited either. For this purpose, especially alginates, polysaccharides, caseins, inorganic disintegration aids such as ben-tonite, but particuiarly cellulose and and cellulose derivatives such as sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, crospovi-done, pregelatinised starch and sodium carboxymethyl starch may be mentioned.
An especially preferred disintegrant is sodium carboxymethyl starch, for example the products available under the tradename Explotab.
Contrary to the pharmaceutical preparations prepared by wet granulation in the prior art, it is not necessary to use a very large amount of disintegrant for the pharmaceutical preparations of the invention. For example, the amount of disin-tegrant is less than 4 %, more preferably less than 3 %, most preferably less than 2.5 %, e.g. about 2 %. As a rule, however, at least 0.1 %, more preferably at least 0.5 % and most preferably at least 1 % of disintegrant is present.
The pharmaceutical preparation of the invention usually contains additional pharmaceutical adjuvants such as fillers, especially inorganic calcium com-pounds, calcium hydrogen phosphate being especially preferred. Other calcium phosphates may also be used. Other suitable fillers are sugars such as lactose or mannitol and well-known cellulose and cellulose derivatives, especially micro-crystalline cellulose, but also starch, corn starch or pregelatinised starch and cyclodextrines. Especially preferred are mixtures of several fillers, for example a mixture of an inorganic calcium compound such as calcium phosphate or cal-ciumhydrogen phosphate and microcrystalline cellulose. In particular, the fillers may be selected to improve the processing characteristics of the pharmaceutical preparations of the invention. For example, a coarse-grained microcrystalline cellulose may be used to improve the flow properties of the mixtures, which may be advantageous especially in direct compression (or the preparation of a tablet by direct compaction, respectively). Microcrystalline celluloses of the Avicel type such as e.g. Avicel PH 101 or Avicel PH 200 are preferred for use as microcrys-talline cellulose. Avicel PH 200 or larger microcrystalline types of cellulose are especially suitable for direct compression or the preparation of tablets by direct compaction, respectively, especially in combination with inorganic calcium com-pounds.
The pharmaceutical preparations of the invention may also contain surfactants and wettings agents, respectively. Contrary to pharmaceutical preparations of the prior art prepared by wet granulation, it is not absolutely necessary to use a wet-ting agent. In particular, it is not necessary to use an alkyl sulfate like the sodium dodecyl sulfate especially preferred in EP-A 969 832. Therefore, if the pharma-ceutical preparations of invention contain surfactants or wetting agents, respec-tively, these are preferably different from alkyl sulfates. In particula, these are not sodium alkyl sulfates such as sodium dodecyl sulfate. Preferred wetting agents are salts of bile acids, acyl sarcosines, polysorbates, polyoxyethylene fatty alco-hol ether, polyethylene glycols and synthetic block copolymers of ethylene oxide and propylene oxide such as the well-known poloxamer. Poloxamer is especially preferred. It goes without saying that mixtures of several compounds may be used.
If surfactants or wetting agents are used, they are usually present in the custom-ary amounds, e.g. an amount of 0.01 to 1 10, especially 0.05 to 0.5 %.
The pharmaceutical preparations of the invention may also contain additional customary pharmaceutical adjuvants as disclosed, for example in EP-A 969 832, e.g. lubricants such as fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oils such as hydrogenated castor oil, polyethylene glycols such as polyethylene gly-col, sodium benzoate, talcum, silicic acids obtained by the pyrogenic route, highly dispersed silica, degreased milk powder or paraffine. If present, the lubricants are found in the pharmaceutical preparations of the invention in the usual amounts of 0.2 to 5 %, especially 0.2 to 3 %.
Other customary adjuvants that may be present in the pharmaceutical prepara-tions of the invention are release agents such as silicon-containing compounds, for example silicic acid or talcum (for example with a weight percentage of 0 % to %) as well as flow agents such as anhydrous colloidal silica or precipitated sil-ica which may be present in an amount of 0 % to 15 %.
Other customary pharmaceutical adjuvants comprise colouring agents, flavouring agents, etc.
Pharmaceutical preparations obtained according to the invention may also be coated, for example to prepare film or lacquer tablets or sugar-coated tablets, respectively. Preferred coatings comprise sugar, polymers (e.g. polymethacry-lates) or cellulose derivatives and, optionally, additional adjuvants.
The pharmaceutical preparations may be prepared in a manner known per se.
For example, the dry compounds may be prepared by simple mixing in a custom-ary dry mixer (e.g. the free-falling mixer Glatt CML10) and subsequent filling of the dry mixture into hard gelatine capsules, sachets etc. Altematively, the mixture may be subjected to dry granulation in the usual manner, and the granules may then either be filled into hard gelatine capsules or sachets as well or compressed to tablets. In addition to filling into hard gelatine capsules, the powder or granules may of course be filled into other containers and processed to soft gelatine cap-sules in the usual known manner.
However, it is especially preferred for the invention to prepare tablets by direct compression. Such direct compaction methods are well known in the prior art and described, for example, in the standard work "Die Tablette" by Ritschel and Bauer-Brandl, Edition Cantor Verlag 2002. How to make the pharmaceutical preparation of the invention is also illustrated in the following examples.
The tablets of the invention surprisingly have better breaking strength than tablets obtained by wet granulation according to the examples of EP-A 969 832. Tablets having a breaking strength of at least 95 N, more preferably of at least 100 N
are preferred for the invention. The breaking strength may be determined in the usual manner according to Pharm. Eur. 2.9.8.
Pharmaceutical preparations comprising the following components are preferred for the invention:
a) Rimonabant Microcrystalline cellulose Calcium hydrogen phosphate NA-carboxymethyl starch Copovidone Lubricant b) Rimonabant Microcrystalline cellulose Lactose monohydrate NA-carboxymethyl starch Copovidone Lubricant c) Rimonabant Microcrystalline cellulose Calcium hydrogen phosphate NA-Carboxymethyl starch Copovidone Polysorbate Lubricant d) Tablet core as in example a) Film coating: polymethacrylate; polyethylene glycol, talcum The following examples illustrate the invention.
Example 1 Preparation of the active ingredient 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1 H-pyrazol-carboxamide ("free base") was synthesised according to EP-A 969 832, example 1. Characterisation by'H-NMR, IR, melting point (155.7 C), HPLC, XRD. The Polymorph I as defined in WO 03/040105 is obtained.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1 H-pyrazol-carboxamide-chlorohydrate ("HCI salt") was synthesised according to EP-A
969 832, example 3. Characterisation by'H-NMR, I R, melting point (227.1 C), chloride content 6.94 0.72 %. The X-ray diffractogram is shown in Fig. 1.
The grain size distribution curve was recorded in three independent measure-ments by means of laser diffractometry (Mastersizer Microplus, Malvern Instru-ments). The grain size is given below in the following percentile values: an upper average (D80), the mean particle diameter (D50) and a lower average (D,o). Mi-cronisation was carried out in an air jet mill (MC Jetmill 50) for 60 - 65 sec. at 2.0 bar nitrogen.
The synthesised base had heterogeneous aggregates (D,o 1.7 pM; D50 10.2 pM;
Dso 30.3 pM). A homogeneous powder was obtained by slurrying in water and ultrasound treatment (D,o 1.3 pM; D50 6.0 pM; D80 14.2 pM).
The synthesised hydrochloride salt was highly heterogeneous with large aggre-gates (D,o 1.1 pM; D50 33.7 pM; DBO 81.3 pM). By slurrying in water and ultra-sound treatment another homogeneous powder was obtained (D,o 0.5 pM; D50 1.2 pM; D80 10.0 pM).
XRDs after micronisation show that the polymorph and crystallinity are preserved.
For the pharmaceutical preparation of example 2, active ingredient particles with the following size distribution were prepared. Mean particle diameter (D50) after micronisation:
- Base 3.3 pM (D,o 0.9 pM; D80 7.4 pM).
- HCI salt 2.9 pM (D,o 1.0 pM; DSO 4.9 pM).
Example 2 Composition of the pharmaceutical preparation Five mixtures with the active ingredient and pharmaceutical additives were pre-pared according to the following table. The mixture A corresponds to the formula-tion F from EP-A 969 832 (Table 6). Mixture B is composed analogously, but con-tains Rimonabant hydrochloride instead of the free base of the active ingredient.
Both mixtures A and B were processed further by wet granulation. The mixtures C, D, and E correspond to the pharmaceutical preparations of the invention which were processed by dry mixing methods only without wet granulation.
Composition A B C D E
Component Function [%] 1%] 1%] 1%] 1%]
Rimonabant base 16.8 16.7 16.7 Active ingredient Rimonabant HCI 17.9 17.8 Active ingredient Amidon DE (corn starch) 28.5 28 2 Filler Avicel PH 101 (MCC) Filler 50.3 49.6 Avicel PH 200 Filler 50.3 Granulac 200 (Lactose monohydrate) 46.4 45.8 Filler DiCafos P
(Calcium hydrogen phosphate) 27.8 27.4 Filler DiCafos (Calcium hydrogen phosphate) 27.8 Filler Ac-Di-Sol (Na-Croscarmelose) 4.8 4.7 Disintegrant Explotab (Na-Carboxymethyl starch) 1.9 1.9 1.9 Disinte rant Kollidon 30 (Povidon K 30) 2.4 2.4 Adhesive/Binderl Kollidon VA 64 (Copovidon) 2,4 2.4 2.4 Adhesive/Binder Sodium dodecyl sulfate 0.1 0.1 Wetting a ent Purified Water Granulation liquid q=s. q.s.
Magnesium stearate Lubricant 1.0 0.9 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0 100.0 The formulations A and B were prepared by wet granulation. Wet granulation was carried out with purified water for four minutes, followed by drying at 50 C
for 6 hrs. and sieving to 1000 pM. The granules were mixed with magnesium stearate for 10 min. at 45 upm and filled into hard gelatine capsules.
The formulations C and D were prepared by simple mixing of the components in a mortar for 4 min. and the pharmaceutical preparation then also filled into hard gelatine capsules. Each hard gelatine capsule contained approx. 180 mg of ac-tive ingredient:
The capsules thus obtained were tested for release of the active ingredient by the methods described in EP-A 969 832. The medium used was 1000 ml 10 ml 0.1 regular citrate phosphate buffer with 0.2 % of SDS at a pH of 3.0 and 37 C. A
standard paddle apparatus (USP-App. II, Distek Premiere 5100) was used at 100 rpm. The release of the Rimonabant was measured by UV at 276 nm. The result is shown as Fig. 2 Example 3 Preparation of tablets From granules prepared by wet granulation of the formulations A and B as de-scribed in example 2, round bevelled tablets having a diameter of 8.0 mm were prepared with a Korsch EKO press. The active ingredient content was about 30 mg in both cases. From the components of formulation E shown in example 2, tablets were prepared by direct compression. For this purpose, all of the compo-nents except magnesium stearate were sieved through 500 pM sieve and mixed for 20 minutes. After addition of magnesium stearate (also sieved through the 500 pM sieve) mixing was continued for another 5 minutes and the mixture then processed to tablets containing about 30 mg of the active ingredient and having a diameter of 8.0 mm, also in a Korsch EKO-Presse.
The breaking strength of the tablets was determined and is summarised in the following table.
A B E
Compressions strength [kN] - 5.8 - 5.8 - 5.9 Compression pressure [mPa] - 110.0 - 110.0 -110.0 Tablet weight* [mg] 179.3 181.7 180.3 Breaking strenghth* [N] 86.9 69.5 104.9 Tablet height* [mm] 2.80 2.79 2.56 The release of the active ingredient from the tablet E of the invention meets the pharmaceutical requirements for a fast-release tablet (85 % release within 15 min.) (Fig. 3).
Therefore, it is the object of the present invention to provide solid pharmaceutical preparations with the active ingredient Rimonabant for oral administration the release behaviour of which is at least as good as that of the oral pharmaceutical preparations of the prior art as descibed, for example, in EP-A 969 832.
However, these pharmaceutical preparations should be easier to prepare than the pharma-ceutical preparations known from EP-A 969 832 and, when they are tablets, they should have better breaking strength than the known tablets.
This object is achieved by the subject matter of the claims.
According to the invention, it was surprisingly found that the problems in connec-tion with the release of Rimonabant from solid pharmaceutical preparations do not occur when the components are mixed in the dry state instead of using a wet granulation process for their manufacture. Optionally, dry granulation may be carried out and, especially for the preparation of tablets, direct compression (i.e.
processing of the dry mixture into tablets by direct compaction). The pharmaceu-tical preparations prepared according to the invention which are obtained by sim-ply dry-mixing the components of the pharmaceutical preparation exhibit excel-lent release profiles which meet the standards required by law, comparable with the release profiles of the pharmaceutical preparations prepared by the wet granulation process of the prior art according to EP-A 969 832. It is not necessary to use very high levels of disintegrants as deemed necessary for the wet granula-tion process of EP-A 969 832, nor is the use of an alkyl sulfate as a wetting agent or surfactant necessary for the pharmaceutical preparations of the invention to achieve the desirable high release of the active ingredient from the pharmaceuti-cal preparations. By working without a wet granulation process, advantages of process technology also result. It is obvious that wet granulation has a negative impact on the release of the active ingredient which must be offset by a large amount of disintegrant and a special surfactant. This negative impact can be avoided by processing the ingredients in the dry state without wet granulation.
Finally, it was surprising to find that better hardness of the tablets is achieved for tablets not prepared by a wet granulation process, but according to the invention by dry-mixing the components and direct compression, than the for tablets dis-closed by way of example in EP-A 969 832.
The pharmaceutical preparations of the invention contain the compound Rimo-nabant, a salt of this compound, a solvate of the compound or a solvate of a salt of this compound. Rimonabant in the form of a base or in the form of the hydro-chloride salt is especially preferred as the active ingredient. Other preferred salts of Rimonabant are the methane sulfonate, the hemifumarate, the p-toluene sul-fonate, the hydrogen sulfate, the dihydrogen phosphate, the hydrobromide, the sulfate, the methyl sulfate, the oxalate, the maleate, the fumarate, the 2-naph-thalene sulfonate, the glyconate, the gluconate, the citrate and the isethionate of the Rimonabant. Especially preferred solvates are the ethanol solvate and the acetone hemisolvate. Particularly preferred are the ethanol solvate of the hydro-chloride salts of the Rimonabant and the ethanol solvate of the Rimonabant in the form of a base. Especially the methane sulfonate may also be present as acetone hemisolvate.
As far as reference is made to Rimonabant or the "active ingredient" in the follow-ing description, this should be understood to mean Rimonabant in the form of the free base or in the form of a salt or solvate or of a solvate of the salt as described above.
The percentage of the active ingredient in the pharmaceutical preparation accord-ing to the invention is usually 0.5 to 50 wt.-%, more preferably 1 to 30 wt.-%, even more preferably 1 to 20 wt.-%, especially 5 to 20 wt.-% and most preferably to 20 wt.-%. A common dosage unit of the pharmaceutical preparation accord-ing to the invention therefore preferably contains 2 mg to 100 mg, more prefera-bly 2 mg to 60 mg, especially 15 mg to 40 mg, e.g. 10, 15, 20, 25 or 30 mg of the active ingredient.
In this application, percentages and portions are always based on the weight of the pharmaceutical preparation unless otherwise indicated or obvious from the context. If an amound of the active ingredient is mentioned, this should be under-stood to mean - in accordance with the above observation - the amount of Rimo-nabant as a base if the Rimonabant is used as a base. If the Rimonabant is used as a salt or solvate or solvate of a salt, this means the amount of the salt, the solvate or the solvate of the salt.
Rimonabant may be present in different polymorphous forms. According to the invention, any polymorphous form, any amorphous form and mixtures of poly-morphous forms with each other and with an amorphous form may be used. The polymorphous form I resulting from the method of EP-A 656 354 is especially preferred for the invention. Also preferred is the polymorph II described in WO
2003/040105. A powder diffractogram of the hydrochloride salte of the Rimona-bant prepared according to example 3 of EP-A 656 354 is enclosed as Fig. 1.
This form of the active ingredient Rimonabant is also preferred for the invention.
Rimonabant is preferabiy used in micronised form in the invention.
Micronisation can be carried out in the usual manner, for example with an air jet mill. The active ingredient particles thus micronised may, for example, be homogenised by ultra-sound treatment. While very small active ingredient particules are used for the wet granulation process, larger particles of the active ingredient may be used for the pharmaceutical preparations of the invention. Especially for the preparation of tablets by direct compression, it may be advantageous to use larger active ingre-dient particles, because the flowability and the processability of the mixture in direct compression is improved. This is another advantage of the invention, be-cause the economic and technical cost of preparing larger particles is lower than the cost of recovering very small particles.
According to the invention, it is preferred that the particle diameter of 50 %
of the active ingredient particles used (D50) is 2 NM or more, more preferably 2,5 pM
or more and especially about 3 pM. The size of 80 % of the active ingredient parti-cles (D80) should advantageously not exceed 80 pM, but preferably 50 % of the particles are not larger than 10 pM and especially not larger than 6 pM. Espe-cially preferably, the D50 value of the active ingredient particles in the pharmaceu-tical preparation of the invention is therefore in the range of 2,5 pM to 6 pM, par-ticularly about 3 pM. Within these ranges, excellent release is achieved on the one hand and good processability, especially in direct compression, on the other.
In addition to the active ingredient, the pharmaceutical preparation according to the invention also contains at least one binder and at least one disintegrant.
The suitable binders are not especially limited; the customary binders known in the prior art may be used. Especially preferred binders are copovidone, povidone, alginic acid and alginates (such as sodium alginate), cellulose and cellulose de-rivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or methyl cellu-lose and hydroxypropyl cellulose with a low level of substitution), gelatine and acrylic acid polymers. The binder copovidone is especially preferred, and the commercial product Kollidon VA 64 may be mentioned as an example. Among the povidones, the commercial product Povidon K 30 is worth mentioning.
The binder content in the pharmaceutical preparation according to the invention is not particularly limited and may be easily selected by a skilled practitioner de-pending on the particular pharmaceutical preparation. Usually the portion of the binder is the range of 0.5 to 10 10, preferably in the range of 0.5 to 5%, espe-cially in the range of 1 to 5%.
The disintegrant used is not particularly limited either. For this purpose, especially alginates, polysaccharides, caseins, inorganic disintegration aids such as ben-tonite, but particuiarly cellulose and and cellulose derivatives such as sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, crospovi-done, pregelatinised starch and sodium carboxymethyl starch may be mentioned.
An especially preferred disintegrant is sodium carboxymethyl starch, for example the products available under the tradename Explotab.
Contrary to the pharmaceutical preparations prepared by wet granulation in the prior art, it is not necessary to use a very large amount of disintegrant for the pharmaceutical preparations of the invention. For example, the amount of disin-tegrant is less than 4 %, more preferably less than 3 %, most preferably less than 2.5 %, e.g. about 2 %. As a rule, however, at least 0.1 %, more preferably at least 0.5 % and most preferably at least 1 % of disintegrant is present.
The pharmaceutical preparation of the invention usually contains additional pharmaceutical adjuvants such as fillers, especially inorganic calcium com-pounds, calcium hydrogen phosphate being especially preferred. Other calcium phosphates may also be used. Other suitable fillers are sugars such as lactose or mannitol and well-known cellulose and cellulose derivatives, especially micro-crystalline cellulose, but also starch, corn starch or pregelatinised starch and cyclodextrines. Especially preferred are mixtures of several fillers, for example a mixture of an inorganic calcium compound such as calcium phosphate or cal-ciumhydrogen phosphate and microcrystalline cellulose. In particular, the fillers may be selected to improve the processing characteristics of the pharmaceutical preparations of the invention. For example, a coarse-grained microcrystalline cellulose may be used to improve the flow properties of the mixtures, which may be advantageous especially in direct compression (or the preparation of a tablet by direct compaction, respectively). Microcrystalline celluloses of the Avicel type such as e.g. Avicel PH 101 or Avicel PH 200 are preferred for use as microcrys-talline cellulose. Avicel PH 200 or larger microcrystalline types of cellulose are especially suitable for direct compression or the preparation of tablets by direct compaction, respectively, especially in combination with inorganic calcium com-pounds.
The pharmaceutical preparations of the invention may also contain surfactants and wettings agents, respectively. Contrary to pharmaceutical preparations of the prior art prepared by wet granulation, it is not absolutely necessary to use a wet-ting agent. In particular, it is not necessary to use an alkyl sulfate like the sodium dodecyl sulfate especially preferred in EP-A 969 832. Therefore, if the pharma-ceutical preparations of invention contain surfactants or wetting agents, respec-tively, these are preferably different from alkyl sulfates. In particula, these are not sodium alkyl sulfates such as sodium dodecyl sulfate. Preferred wetting agents are salts of bile acids, acyl sarcosines, polysorbates, polyoxyethylene fatty alco-hol ether, polyethylene glycols and synthetic block copolymers of ethylene oxide and propylene oxide such as the well-known poloxamer. Poloxamer is especially preferred. It goes without saying that mixtures of several compounds may be used.
If surfactants or wetting agents are used, they are usually present in the custom-ary amounds, e.g. an amount of 0.01 to 1 10, especially 0.05 to 0.5 %.
The pharmaceutical preparations of the invention may also contain additional customary pharmaceutical adjuvants as disclosed, for example in EP-A 969 832, e.g. lubricants such as fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oils such as hydrogenated castor oil, polyethylene glycols such as polyethylene gly-col, sodium benzoate, talcum, silicic acids obtained by the pyrogenic route, highly dispersed silica, degreased milk powder or paraffine. If present, the lubricants are found in the pharmaceutical preparations of the invention in the usual amounts of 0.2 to 5 %, especially 0.2 to 3 %.
Other customary adjuvants that may be present in the pharmaceutical prepara-tions of the invention are release agents such as silicon-containing compounds, for example silicic acid or talcum (for example with a weight percentage of 0 % to %) as well as flow agents such as anhydrous colloidal silica or precipitated sil-ica which may be present in an amount of 0 % to 15 %.
Other customary pharmaceutical adjuvants comprise colouring agents, flavouring agents, etc.
Pharmaceutical preparations obtained according to the invention may also be coated, for example to prepare film or lacquer tablets or sugar-coated tablets, respectively. Preferred coatings comprise sugar, polymers (e.g. polymethacry-lates) or cellulose derivatives and, optionally, additional adjuvants.
The pharmaceutical preparations may be prepared in a manner known per se.
For example, the dry compounds may be prepared by simple mixing in a custom-ary dry mixer (e.g. the free-falling mixer Glatt CML10) and subsequent filling of the dry mixture into hard gelatine capsules, sachets etc. Altematively, the mixture may be subjected to dry granulation in the usual manner, and the granules may then either be filled into hard gelatine capsules or sachets as well or compressed to tablets. In addition to filling into hard gelatine capsules, the powder or granules may of course be filled into other containers and processed to soft gelatine cap-sules in the usual known manner.
However, it is especially preferred for the invention to prepare tablets by direct compression. Such direct compaction methods are well known in the prior art and described, for example, in the standard work "Die Tablette" by Ritschel and Bauer-Brandl, Edition Cantor Verlag 2002. How to make the pharmaceutical preparation of the invention is also illustrated in the following examples.
The tablets of the invention surprisingly have better breaking strength than tablets obtained by wet granulation according to the examples of EP-A 969 832. Tablets having a breaking strength of at least 95 N, more preferably of at least 100 N
are preferred for the invention. The breaking strength may be determined in the usual manner according to Pharm. Eur. 2.9.8.
Pharmaceutical preparations comprising the following components are preferred for the invention:
a) Rimonabant Microcrystalline cellulose Calcium hydrogen phosphate NA-carboxymethyl starch Copovidone Lubricant b) Rimonabant Microcrystalline cellulose Lactose monohydrate NA-carboxymethyl starch Copovidone Lubricant c) Rimonabant Microcrystalline cellulose Calcium hydrogen phosphate NA-Carboxymethyl starch Copovidone Polysorbate Lubricant d) Tablet core as in example a) Film coating: polymethacrylate; polyethylene glycol, talcum The following examples illustrate the invention.
Example 1 Preparation of the active ingredient 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1 H-pyrazol-carboxamide ("free base") was synthesised according to EP-A 969 832, example 1. Characterisation by'H-NMR, IR, melting point (155.7 C), HPLC, XRD. The Polymorph I as defined in WO 03/040105 is obtained.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1 H-pyrazol-carboxamide-chlorohydrate ("HCI salt") was synthesised according to EP-A
969 832, example 3. Characterisation by'H-NMR, I R, melting point (227.1 C), chloride content 6.94 0.72 %. The X-ray diffractogram is shown in Fig. 1.
The grain size distribution curve was recorded in three independent measure-ments by means of laser diffractometry (Mastersizer Microplus, Malvern Instru-ments). The grain size is given below in the following percentile values: an upper average (D80), the mean particle diameter (D50) and a lower average (D,o). Mi-cronisation was carried out in an air jet mill (MC Jetmill 50) for 60 - 65 sec. at 2.0 bar nitrogen.
The synthesised base had heterogeneous aggregates (D,o 1.7 pM; D50 10.2 pM;
Dso 30.3 pM). A homogeneous powder was obtained by slurrying in water and ultrasound treatment (D,o 1.3 pM; D50 6.0 pM; D80 14.2 pM).
The synthesised hydrochloride salt was highly heterogeneous with large aggre-gates (D,o 1.1 pM; D50 33.7 pM; DBO 81.3 pM). By slurrying in water and ultra-sound treatment another homogeneous powder was obtained (D,o 0.5 pM; D50 1.2 pM; D80 10.0 pM).
XRDs after micronisation show that the polymorph and crystallinity are preserved.
For the pharmaceutical preparation of example 2, active ingredient particles with the following size distribution were prepared. Mean particle diameter (D50) after micronisation:
- Base 3.3 pM (D,o 0.9 pM; D80 7.4 pM).
- HCI salt 2.9 pM (D,o 1.0 pM; DSO 4.9 pM).
Example 2 Composition of the pharmaceutical preparation Five mixtures with the active ingredient and pharmaceutical additives were pre-pared according to the following table. The mixture A corresponds to the formula-tion F from EP-A 969 832 (Table 6). Mixture B is composed analogously, but con-tains Rimonabant hydrochloride instead of the free base of the active ingredient.
Both mixtures A and B were processed further by wet granulation. The mixtures C, D, and E correspond to the pharmaceutical preparations of the invention which were processed by dry mixing methods only without wet granulation.
Composition A B C D E
Component Function [%] 1%] 1%] 1%] 1%]
Rimonabant base 16.8 16.7 16.7 Active ingredient Rimonabant HCI 17.9 17.8 Active ingredient Amidon DE (corn starch) 28.5 28 2 Filler Avicel PH 101 (MCC) Filler 50.3 49.6 Avicel PH 200 Filler 50.3 Granulac 200 (Lactose monohydrate) 46.4 45.8 Filler DiCafos P
(Calcium hydrogen phosphate) 27.8 27.4 Filler DiCafos (Calcium hydrogen phosphate) 27.8 Filler Ac-Di-Sol (Na-Croscarmelose) 4.8 4.7 Disintegrant Explotab (Na-Carboxymethyl starch) 1.9 1.9 1.9 Disinte rant Kollidon 30 (Povidon K 30) 2.4 2.4 Adhesive/Binderl Kollidon VA 64 (Copovidon) 2,4 2.4 2.4 Adhesive/Binder Sodium dodecyl sulfate 0.1 0.1 Wetting a ent Purified Water Granulation liquid q=s. q.s.
Magnesium stearate Lubricant 1.0 0.9 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0 100.0 The formulations A and B were prepared by wet granulation. Wet granulation was carried out with purified water for four minutes, followed by drying at 50 C
for 6 hrs. and sieving to 1000 pM. The granules were mixed with magnesium stearate for 10 min. at 45 upm and filled into hard gelatine capsules.
The formulations C and D were prepared by simple mixing of the components in a mortar for 4 min. and the pharmaceutical preparation then also filled into hard gelatine capsules. Each hard gelatine capsule contained approx. 180 mg of ac-tive ingredient:
The capsules thus obtained were tested for release of the active ingredient by the methods described in EP-A 969 832. The medium used was 1000 ml 10 ml 0.1 regular citrate phosphate buffer with 0.2 % of SDS at a pH of 3.0 and 37 C. A
standard paddle apparatus (USP-App. II, Distek Premiere 5100) was used at 100 rpm. The release of the Rimonabant was measured by UV at 276 nm. The result is shown as Fig. 2 Example 3 Preparation of tablets From granules prepared by wet granulation of the formulations A and B as de-scribed in example 2, round bevelled tablets having a diameter of 8.0 mm were prepared with a Korsch EKO press. The active ingredient content was about 30 mg in both cases. From the components of formulation E shown in example 2, tablets were prepared by direct compression. For this purpose, all of the compo-nents except magnesium stearate were sieved through 500 pM sieve and mixed for 20 minutes. After addition of magnesium stearate (also sieved through the 500 pM sieve) mixing was continued for another 5 minutes and the mixture then processed to tablets containing about 30 mg of the active ingredient and having a diameter of 8.0 mm, also in a Korsch EKO-Presse.
The breaking strength of the tablets was determined and is summarised in the following table.
A B E
Compressions strength [kN] - 5.8 - 5.8 - 5.9 Compression pressure [mPa] - 110.0 - 110.0 -110.0 Tablet weight* [mg] 179.3 181.7 180.3 Breaking strenghth* [N] 86.9 69.5 104.9 Tablet height* [mm] 2.80 2.79 2.56 The release of the active ingredient from the tablet E of the invention meets the pharmaceutical requirements for a fast-release tablet (85 % release within 15 min.) (Fig. 3).
Claims (20)
1. A pharmaceutical preparation for oral administration of the active ingredi-ent 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazol-3-carboxamide or a salt or solvate thereof or a solvate of the salt of the active ingredient, obtainable by dry-mixing and, optionally, by dry granulation or direct compression with exclusion of a wet granulation process, of 0.5 to 50 wt.-% of the active ingredient or the salt or solvate thereof or the solvate of the salt of the active ingredient, at least one binder, at least one disintegrant and, optionally, additional pharmaceutical adjuvants.
2. A pharmaceutical preparation according to claim 1, characterised in that the active ingredient is present in the form of the hydrochloride salt or a solvate of the hydrochloride salt.
3. A pharmaceutical preparation according to claim 1 or 2, characterised in that it either does not contain a wetting agent or contains a wetting agent different from an alkyl sulfate.
4. A pharmaceutical preparation according to claim 3, characterised in that it contains one or more wetting agents, selected from the salts of bile acids, acyl sarcosines, polysorbates, polyoxyethylene fatty alcohol ethers, poly-ethylene glycols and synthetic block copolymers of ethylene oxide and propylene oxid.
5. A pharmaceutical preparation according to any of the claims 1 to 4, char-acterised in that the active ingredient or the salt or the solvate thereof or the solvate of the salt of the active ingredient is present in micronised form.
6. A pharmaceutical preparation according to claim 5, characterised in that the mean grain size of the active ingredient or the salt or solvate thereof or the solvate of the salt of the active ingredient is 2.5 pm or more.
7. A pharmaceutical preparation according to any of the claims 1 to 6, char-acterised in that the content of the disintegrant is in the range of 0.1 to 2 wt.-% based on the total weight of the pharmaceutical preparation.
8. A pharmaceutical preparation according to any of the claims 1 to 7, char-acterised in that it is a tablet.
9. A pharmaceutical preparation according to claim 8, characterised in that it is a tablet prepared by direct compression.
10. A pharmaceutical preparation according to claim 9, characterised in that the tablet has a breaking strength of at least 95 N.
11. A pharmaceutical preparation according to any of the claims 1 to 7, char-acterised in that it is a hard gelatine capsule containing the mixture as a powder or granules.
12. A method for preparing a pharmaceutical preparation for oral administra-tion of the active ingredient 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazol-3-carboxamide or a salt or solvate thereof or a solvate of the salt of the active ingredient, characterised in that 0.5 to 50 wt.-% of active ingredient, at least one binder, at least one disintegrant and, optionally, additional pharmaceutical adjuvants are dry-mixed and, if necessary, subjected to dry granulation or direct compres-sion, said process not comprising any wet granulation.
13. A method according to claim 12, characterised in that the active ingredient is used as the hydrochloride salt or as the solvate of the hydrochloride salt.
14. A method according to claim 12 or 13, characterised in that the pharma-ceutical preparation either does not contain a wetting agent or a wetting agent which is different from an alkyl sulfate.
15. A method according to claim 14, characterised in that the pharmaceutical preparation contains one or more wetting agents selected from the salts of bile acids, acyl sarcosines, polysorbates, polyoxyethylene fatty alcohol ethers, polyethylene glycols and synthetic block copolymers of ethylene oxide and propylene oxide.
16. A method according to any of the claims 12 to 15, characterised in that the active ingredient or the salt or the solvate thereof or the solvate of the salt of the active ingredient is present in micronised form.
17. A method according to claim 16, characterised in that the active ingredient or the salt or solvate thereof or the solvate of the salt of the active ingredi-ent has a mean grain size of at least 2.5 µm.
18. A method according to any of the claims 12 to 17, characterised in that the pharmaceutical preparation has a disintegrant content of 0.1 to 2.5 wt.-% based on the total weight of the pharmaceutical preparation.
19. A method according to any of the claims 12 to 18, characterised in that the pharmaceutical preparation is a tablet.
20. A method according to claim 19, characterised in that it comprises the process step of direct compression.
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EP06016450A EP1886684A1 (en) | 2006-08-07 | 2006-08-07 | Pharmaceutical composition comprising rimonabant |
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---|---|---|---|---|
FR2758723B1 (en) * | 1997-01-28 | 1999-04-23 | Sanofi Sa | USE OF CENTRAL CANNABINOID RECEPTOR ANTAGONISTS FOR THE PREPARATION OF DRUGS |
FR2837706A1 (en) * | 2002-03-28 | 2003-10-03 | Sanofi Synthelabo | USE OF A CB1 CANNABINOID RECEPTOR ANTAGONIST FOR THE PREPARATION OF MEDICINES USEFUL FOR THE TREATMENT OF SEXUAL DYSFUNCTION AND / OR IMPROVING SEXUAL PERFORMANCE |
US20040122033A1 (en) * | 2002-12-10 | 2004-06-24 | Nargund Ravi P. | Combination therapy for the treatment of obesity |
-
2006
- 2006-08-07 EP EP06016450A patent/EP1886684A1/en not_active Withdrawn
-
2007
- 2007-08-06 CA CA 2596153 patent/CA2596153A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP1886684A1 (en) | 2008-02-13 |
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